Autoimmune endocrine disease
Philip E. Harris, Pierre-Marc G. Bouloux in Endocrinology in Clinical Practice, 2014
The etiologies of Hashimoto’s thyroiditis and GD remain uncertain, but they are likely the result of both genetic and acquired factors.3 Perhaps our best clues about the relative importance of each derive from twin studies in which GD affects either one or both monozygotic twins.9 Those studies point to about a 30% genetic contribution. Frequently, the HLA-DR3 genotype is found in these patients. Several candidate susceptibility genes have been proposed as being associated with thyroid autoimmunity. Among these genes are CTLA-4, CD40, PTPN22, and FCRL3.10 The evidence for each being involved in the pathogenesis of disease has been reviewed extensively elsewhere. Importantly, no convincing evidence yet exists for any of these candidates targeting individuals for disease-specific manifestations associated with either GD or Hashimoto’s thyroiditis. Thus, factors other than those arising from genetic makeup might provide disease-specific susceptibility. With regard to the nongenetic factors, stress, diet, pollutants, and infectious agents have all been mentioned, but the successful identification of specific factors as causative in GD remains an unmet objective. Nonetheless, tobacco smoking has been identified as a major risk factor for developing GD.11 In a study of monozygotic twins both of whom smoked, the twin with the greater exposure to cigarettes was more likely to manifest GD.
Other Inherited Disorders of the Thyroid System
Geraldo Medeiros-Neto, John Bruton Stanbury in Inherited Disorders of the Thyroid System, 2019
The link between an autoimmune disease and the HLA system became evident with the observation that the antigen HLA-B8 occurred in GD with approximately twice the incidence observed in a control population.24 Later it was found that GD in Caucasians is primarily associated with HLA-DR3.25,26 Inheritance of HLA-DR3 carries an up to sixfold increased risk for the occurrence of GD or atrophic thyroiditis. Inheritance of HLA-DR5 has a similar association with Hashimoto’s thyroiditis.27 Postpartum thyroiditis is associated with both HLA-DR4 and -DR5.28 The relations between MHC and AITD susceptibility in other ethnic groups other than Caucasians are far from clear. In Chinese from Singapore and Hong Kong GD was related to HLA-Bw46.29 Earlier studies in the Japanese population have suggested an association of GD with HLA-B 35 and this same antigen was also associated with autoimmune thyroiditis. Recent studies with restriction fragment length polymorphism (RFLP) analyses of HLA-DP loci in both idiopathic myxedema and hypothyroidism associated with blocking-type thyrotropin (TSH) receptor antibodies have indicated that idiopathic myxedema patients are characterized by high frequency of HLA-DPw2 and are genetically similar to Hashimoto’s thyroiditis. Subjects with TSH receptor blocking antibodies are genetically similar to those with Graves’ disease.29a In Koreans a similar study demonstrated that increased frequencies of DR8 and DQB 1*0302 were only observed in patients with autoimmune thyroiditis with positive tests for antibodies against the TSH receptor.29b
Diabetes mellitus
David M. Luesley, Mark D. Kilby in Obstetrics & Gynaecology, 2016
Type 1 DM (juvenile onset) is an autoimmune disease that usually presents in childhood or young adulthood. Autoimmune destruction of the pancreatic islet cells results in insulin deficiency and causes symptoms of thirst, polyuria, blurred vision, weight loss and, if untreated, progression to life-threatening diabetic ketoacidosis. There is a genetic component and it is associated with human leukocyte antigen (HLA)-DR3 and HLA-DR4. It is not associated with obesity. The baby of an affected mother has a 2% risk of developing diabetes, whilst the child of an affected father faces an 8% risk. If both parents have type 1 diabetes, there is a 30% risk to their offspring.
Stiff-person syndrome: an atypical presentation and a review of the literature
Published in Hospital Practice, 2021
Benjamin C. Lin, Jaspreet Johal, Keithan Sivakumar, Alissa E. Romano, Hussam A. Yacoub
Evidence for a causative link between anti-GAD antibodies and SPS is supported by in vitro studies showing inhibition of GAD activity with transfer of antibodies prepared from SPS patients’ serum, while antibodies from patients with type-I diabetes did not have the same effect [42]. Antibodies isolated from the CSF of SPS patients reduce the release of GABA from presynaptic terminals [43]. The difference between anti-GAD antibodies found in patients with type 1 diabetes and SPS may be due to targeting different epitopes on the linearized GAD65 enzyme. In SPS, the antibodies target the N-terminal, C-terminal, and middle of the linear GAD-65 epitope. At the N-terminus, they appear to target a specific 8-amino acid epitope which is common to patients with the HLA-DR3 haplotype [44]. In addition, the unique affinity of SPS patients’ anti-GAD antibodies to the C-terminal region appears to decrease enzymatic activity via a noncompetitive mechanism. Studies in animal models demonstrated dose-dependent motor dysfunction given exposure to epitope-specific monoclonal anti-GAD antibody or IgG fraction of a patient with SPS [45,46]. Finally, GABA-enhancing agents such as benzodiazepines and baclofen are found to be helpful in the treatment of SPS.
An inflammatory triangle in Sarcoidosis: PPAR-γ, immune microenvironment, and inflammation
Published in Expert Opinion on Biological Therapy, 2021
Parnia Jabbari, Mona Sadeghalvad, Nima Rezaei
Sarcoidosis is a polygenic disorder, and several genes with different phenotypes are associated with disease development. Although further investigations are needed to determine, certain HLA-alleles have been distinguished to influence susceptibility to sarcoidosis [29]. In 2009, Grunewald J et al. showed that HLA- DRB1*03 (DR3) allele is associated with Löfgren syndrome, a type of acute sarcoidosis. In their study, 301 patients with Löfgren syndrome were included, and the significant association was found between HLA-DR3 allele and disease recovery within 2 years. However, 49% of HLA-DR3 negative patients developed a non-resolving disease [30]. In addition, HLA-DRB1*15 (DR15) and DRB1*14 (DR14) have been recognized to be associated with chronic non-resolving disease [31]. It has been mentioned that among the patients with sarcoid arthritis, HLA-B8 and HLA-B14 are more prevalent alleles and HLA-DRB1*04 is considerably rare. These patients are also carriers for HLA-DR3 allele [7].
HLA transgenic mice: application in reproducing idiosyncratic drug toxicity
Published in Drug Metabolism Reviews, 2020
Takeshi Susukida, Shigeki Aoki, Tomohiro Shirayanagi, Yushiro Yamada, Saki Kuwahara, Kousei Ito
Using HLA-DR3 (DRB1*03:01) transgenic mice, an animal model for Hashimoto's thyroiditis was established via immunization with thyroglobulin, which induces autoimmune thyroiditis (Kong et al. 1996; Flynn et al. 2002; Wan et al. 2002; Karras et al. 2005; Jacob et al. 2007). Likewise, severe thyroiditis was developed in human thyroglobulin-immunized HLA-DR3/NOD mice (Flynn et al. 2001). Both HLA-DR3 and HLA-DR3/NOD mice can serve as model systems for Graves’ hyperthyroid disease, when immunized with plasmid DNA encoding the human thyrotropin receptor (Pichurin et al. 2003; Flynn, Rao, et al. 2004) or thyroid peroxidase, with the addition of either IL-12 or GM-CSF (Flynn, Gardas, et al. 2004). Moreover, HLA-DR3/NOD mice could be developed as a novel model of autoimmune hepatitis (Yuksel et al. 2015).
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